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Molecular and Cellular Biology

Tassa K Saldi, Patrick Gonzales, Alfonso Garrido-Lecca, Vishantie Dostal, Christine M Roberts, Leonard Petrucelli, Christopher D Link
TDP-1 is the C. elegans ortholog of mammalian TDP-43, which is strongly implicated in the etiology of Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS). We discovered that deletion of the tdp-1 gene results in enhanced nuclear RNA interference (RNAi). As nuclear RNAi in C. elegans involves chromatin changes moderated by HPL-2, a homolog of heterochromatin protein 1 (HP1), we investigated the interaction of TDP-1 and HPL-2. We find that TDP-1 and HPL-2 interact directly, and loss of TDP-1 dramatically alters the chromatin association of HPL-2...
May 14, 2018: Molecular and Cellular Biology
Alyssa Ward, Gita Kumari, Ranjan Sen, Stephen Desiderio
Accessibility of antigen receptor loci to RAG is correlated with the presence of H3K4me3, which binds to a plant homeodomain (PHD) in the RAG-2 subunit and promotes V(D)J recombination. A point mutation in the PHD, W453A, eliminates binding of H3K4me3 and impairs recombination. The debilitating effect of the W453A mutation is ameliorated by second-site mutations that locate an inhibitory domain in the interval from 352 through 405 of RAG-2. Disruption of the inhibitory domain stimulates V(D)J recombination within extrachromosomal substrates and at endogenous antigen receptor loci...
May 14, 2018: Molecular and Cellular Biology
Fan Yang, Yang Xing, Yinan Li, Xiaoning Chen, Zhilong Ai, Yuanyan Wei, Jianhai Jiang
CD133, a widely known marker for cancer stem cells, has recently been found in extracellular vesicles. However, the mechanisms underlying CD133 translocation to the extracellular space remain largely unknown. Here, we report that CD133 is mono-ubiquitinated. Ubiquitination occurs primarily on complex glycosylated CD133. Lysine 848 residue at the intracellular carboxyl terminal is one of the sites for CD133 ubiquitination. K848R mutation does not affect CD133 degradation by the lysosomal pathway, but significantly reduces CD133 secretion...
May 14, 2018: Molecular and Cellular Biology
Christina Wei, Lauren Stock, Christiane Schneider-Gold, Claudia Sommer, Nikolai A Timchenko, Lubov Timchenko
Myotonic Dystrophy type 2 (DM2) is a neuromuscular disease caused by an expansion of intronic CCTG repeats in the CNBP gene which encodes a protein regulating translation and transcription. To better understand the role of CNBP in DM2 pathology, we examined skeletal muscle in a new model of Cnbp knock out (KO) mice. This study showed that a loss of Cnbp disturbs myofibrillar sarcomeric organization at birth. Surviving homozygous Cnbp KO mice develop muscle atrophy at young age. Skeletal muscle phenotype in heterozygous Cnbp KO mice was milder, but they develop severe muscle wasting at advanced age...
May 7, 2018: Molecular and Cellular Biology
Osamu Baba, Takahiro Horie, Tetsushi Nakao, Daihiko Hakuno, Yasuhiro Nakashima, Hitoo Nishi, Yasuhide Kuwabara, Masataka Nishiga, Tomohiro Nishino, Yuya Ide, Fumiko Nakazeki, Satoshi Koyama, Masahiro Kimura, Ritsuko Hanada, Masahiro Kawahara, Takeshi Kimura, Koh Ono
MicroRNA (miR)-33 targets ATP-binding cassette transporter A1 (ABCA1), and its deficiency increases serum HDL-cholesterol (HDL-C) and ameliorates atherosclerosis. Although we previously reported that miR-33 deficiency increased peripheral Ly6Chigh monocytes on ApoE-deficient background, the effect of miR-33 on monocyte population is not fully elucidated especially on wild-type (WT) background.We found that Ly6Chigh monocytes in miR-33-/- mice were decreased in peripheral blood and increased in bone marrow (BM)...
April 30, 2018: Molecular and Cellular Biology
Matthew J Brody, Davy Vanhoutte, Tobias G Schips, Justin G Boyer, Chinmay V Bakshi, Michelle A Sargent, Allen J York, Jeffery D Molkentin
Thrombospondins are stress-inducible secreted glycoproteins with critical functions in tissue injury and healing. Thrombospondin-4 (Thbs4) is protective in cardiac and skeletal muscle where it activates an adaptive endoplasmic reticulum (ER) stress-response, induces expansion of the ER, and enhances sarcolemmal stability. However, it is unclear if Thbs4 has these protective functions from within the cell, from the extracellular matrix, or from the secretion process itself. Here we generated transgenic mice with cardiac-specific overexpression of a secretion-defective mutant of Thbs4 to evaluate its exclusive intracellular and secretion-dependent functions...
April 30, 2018: Molecular and Cellular Biology
Bhawana Uprety, Amala Kaja, Sukesh R Bhaumik
TOR (Target of rapamycin) has been previously implicated in transcriptional stimulation of the ribosomal protein (RP) genes via enhanced recruitment of NuA4 (Nucleosome acetyltransferase of H4) to the promoters. However, it is not clearly understood how TOR enhances NuA4 recruitment to the promoters of the RP genes. Here, we show that TOR facilitates the recruitment of the 19S proteasome subcomplex to the activator to enhance the targeting of NuA4 to the promoters of the RP genes. NuA4, in turn, promotes the recruitment of TFIID (Transcription factor IID that is composed of TBP and a set of TBP-associated factors or TAFs) and RNA polymerase II to the promoters of the RP genes to enhance transcriptional initiation...
April 30, 2018: Molecular and Cellular Biology
Rakesh Ganji, Sirisha Mukkavalli, Flavio Somanji, Malavika Raman
A balance between protein synthesis and degradation is necessary to maintain cellular homeostasis. Failure to triage aberrant proteins may result in their accumulation and aggregation in the cytosol. The VCP-BAG6 complex facilitates a wide variety of ubiquitin-mediated quality control events at the ER; both prior to ER translocation as well as during ER associated degradation (ERAD). Yet, how ubiquitylated clients associated with BAG6 are recognized by VCP for proteasomal degradation is presently unknown. We have identified UBXN1 as the VCP adaptor in BAG6-dependent processes occurring prior to ER insertion but not during ERAD...
April 23, 2018: Molecular and Cellular Biology
Jose Mercado-Matos, Jenny Janusis, Sha Zhu, Samuel S Chen, Leslie M Shaw
Although the insulin receptor substrate (IRS) proteins IRS1 and IRS2 share considerable homology and activate common signaling pathways, their contributions to breast cancer are distinct. IRS1 has been implicated in the proliferation and survival of breast tumor cells. In contrast, IRS2 facilitates glycolysis, invasion and metastasis. To determine the mechanistic basis for IRS2-dependent functions, we investigated unique structural features of IRS2 that are required for invasion. Our studies revealed that the ability of IRS2 to promote invasion is dependent upon upstream IGF-1R/IR activation and the recruitment and activation of PI3K, functions shared with IRS1...
April 23, 2018: Molecular and Cellular Biology
Monica Nanni, Danilo Ranieri, Benedetta Rosato, Maria Rosaria Torrisi, Francesca Belleudi
The FGFR2b is a receptor tyrosine kinase expressed exclusively in epithelial cells. We previously demonstrated that FGFR2b induces autophagy and that this process is required for the triggering of FGFR2b-mediated keratinocytes early differentiation. However, the molecular mechanisms regulating this interplay remain to be elucidated. Since we have also recently shown that JNK1 signaling is involved in FGFR2b-induced autophagy and a possible role of JNK pathway in epidermal differentiation has been suggested but it is still debated, here we investigated the crosstalk between FGFR2b-mediated autophagy and differentiation focusing on the downstream JNK signaling...
April 23, 2018: Molecular and Cellular Biology
Fanli Zeng, Yu Hua, Xiaoqin Liu, Sijie Liu, Kejing Lao, Ze Zhang, Daochun Kong
RNA polymerase II (RNAPII) is one of the central enzymes in cell growth and organizational development. It is a large macromolecular complex consisting of twelve subunits. Relative to the clear definition of RNAPII structure and biological function, the molecular mechanism of how RNAPII is assembled is poorly understood, because of that the key assembly factors acting for the assembly of RNAPII remain elusive. In this study, we identified two factors, Gpn2 and Rba50, which directly participate in the assembly of RNAPII...
April 16, 2018: Molecular and Cellular Biology
Mitsuaki Fujimoto, Ryosuke Takii, Arpit Katiyar, Pratibha Srivastava, Akira Nakai
The heat shock response (HSR) is characterized by the rapid and robust induction of heat shock proteins (HSPs), including HSP70, in response to heat shock, and is regulated by heat shock transcription factor 1 (HSF1) in mammalian cells. Poly(ADP-ribose) polymerase 1 (PARP1), which can form a complex with HSF1 through the scaffold protein PARP13, has been suggested to be involved in the HSR. However, its effects on and regulatory mechanisms of the HSR are not well understood. Here, we show that prior to heat shock the HSF1-PARP13-PARP1 complex binds to HSP70 promoter...
April 16, 2018: Molecular and Cellular Biology
Wang-Yang Xu, Houbao Zhu, Yan Shen, Ying-Han Wan, Xiao-Die Tu, Wen-Ting Wu, Lingyun Tang, Hong-Xin Zhang, Shun-Yuan Lu, Xiao-Long Jin, Jian Fei, Zhu-Gang Wang
DHTKD1, a part of 2-ketoadipic acid dehydrogenase complex, is involved in lysine and tryptophan catabolism. Mutations in DHTKD1 block the metabolic pathway and cause 2-aminoadipic and 2-oxoadipic aciduria (AMOXAD), an autosomal recessive inborn metabolic disorder. In addition, a nonsense mutation in DHTKD1 we identified previously causes Charcot-Marie-Tooth disease (CMT) type 2Q, one of the most common inherited neurological disorders affecting the peripheral nerves in the musculature. However, the comprehensive molecular mechanism underlying CMT2Q remains elusive...
April 16, 2018: Molecular and Cellular Biology
Jun-Yao Wang, Yu-Hong Cui, Lan Xiao, Hee Kyoung Chung, Yunzhan Zhang, Jaladanki N Rao, Myriam Gorospe, Jian-Ying Wang
The mammalian intestinal epithelium establishes a selectively permeable barrier that supports nutrient absorption and prevents intrusion by luminal noxious substances and microbiota. The effectiveness and integrity of the barrier function are tightly regulated via well-controlled mechanisms. Long noncoding RNAs transcribed from ultraconserved regions (T-UCRs) control diverse cellular processes, but their roles in the regulation of gut permeability remain largely unknown. Here, we report that the T-UCR uc.173 enhances the intestinal epithelial barrier function by antagonizing microRNA 29b (miR-29b)...
April 9, 2018: Molecular and Cellular Biology
Eunice Domínguez-Martín, Laura Ongay-Larios, Laura Kawasaki, Olivier Vincent, Gerardo Coello, Roberto Coria, Ricardo Escalante
The Unfolded Protein Response (UPR) is an adaptive pathway that restores cellular homeostasis after endoplasmic reticulum (ER) stress. The ER-resident kinase/ribonuclease Ire1 is the only UPR sensor conserved during evolution. Autophagy, a lysosomal degradative pathway, also contributes to the recovery of cell homeostasis after ER-stress but the interplay between these two pathways is still poorly understood. We describe the Dictyostelium discoideum ER-stress response and characterize its single bonafide Ire1 orthologue, IreA...
April 9, 2018: Molecular and Cellular Biology
Philippe P Roux, Ivan Topisirovic
Translation is a key step in the regulation of gene expression and one of the most energy consuming processes in the cell. In response to various stimuli, multiple signaling pathways converge on the translational machinery to regulate its function. To date, the role of phosphoinositide 3-kinase (PI3K)/AKT and the mitogen-activated protein kinase (MAPK) pathways in the regulation of translation is among the best understood. Both pathways engage the mechanistic target of rapamycin (mTOR) to regulate a variety of components of the translational machinery...
April 2, 2018: Molecular and Cellular Biology
Sarah C Williams, Jason L Parsons
Endonuclease III-like protein 1 (NTH1) is a DNA glycosylase required for the repair of oxidised bases, such as thymine glycol, during the base excision repair pathway. We examined regulation of NTH1 protein by the ubiquitin proteasome pathway and have identified the E3 ubiquitin ligase tripartite motif 26 (TRIM26) as the major enzyme targeting NTH1 for polyubiquitylation. We demonstrate that TRIM26 catalyses ubiquitylation of NTH1 predominantly on lysine 67 present within the N-terminus of the protein in vitro In addition, the stability of a ubiquitylation-deficient protein mutant of NTH1 (lysine to arginine) at this specific residue is significantly increased in comparison to the wild type protein when transiently expressed in cultured cells...
April 2, 2018: Molecular and Cellular Biology
Lei Lei, Wenguang Cao, Ling Liu, Urmi Das, Yujia Wu, Guodong Liu, Muhammad Sohail, Yangjun Chen, Jiuyong Xie
The pituitary-derived somatolactotrophe GH3 cells secrete both growth hormone (GH) and prolactin (PRL). We have found that the hnRNP L and L-like (LL) paralogs differentially regulate alternative splicing of genes in these cells. Here we show that hnRNP L is essential for PRL only, but LL for both PRL and GH production. Transcriptome-wide RNA-seq analysis indicates that they differentially control groups of hormone or hormone-related genes involved in hormone production/regulation at total transcript and alternative exon levels...
April 2, 2018: Molecular and Cellular Biology
Dhananjaya D, Kuan-Yang Hung, Woan-Yuh Tarn
The RNA-binding motif 4 (RBM4) protein participates in cell differentiation via its role in regulating the expression of or tissue-specific or developmentally regulated mRNA splice isoforms. RBM4 is expressed in embryonic brain during development; it is initially enriched in the ventricular zone/subventricular zone and subsequently distributed throughout the cortical cortex. Rbm4a knockout brain exhibited delayed migration of late-born neurons. Using in utero electroporation, we confirmed that knockdown of RBM4 impaired cortical neuronal migration...
March 26, 2018: Molecular and Cellular Biology
Lucas J M Bruurs, Mirjam C van der Net, Susan Zwakenberg, Axel Rosendahl Huber, Anneke Post, Fried J Zwartkruis, Johannes L Bos
PTEN is a tumor suppressor frequently lost in epithelial malignancies. Part of the tumor suppressive properties of PTEN is attributed to its function in cell polarization and consequently its role in maintaining epithelial tissue integrity. However, surprisingly little is known about the function and regulation of PTEN during epithelial cell polarization.We used CRISPR/Cas9-mediated gene disruption to delete PTEN in intestinal epithelial Ls174T:W4 cells, which upon differentiation form a microvilli-covered apical membrane (brush border) on a part of the cell cortex, independent of cell-cell junctions...
March 26, 2018: Molecular and Cellular Biology
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